The apoE receptor-2 (apoER2) encoding gene LRP8 is a major gene locus for premature atherosclerosis and acute myocardial infarction. One apoER2 variant with the R952Q mutation (allele frequency 0.29) is associated with a 2-4 fold increase risk of acute myocardial infarction. The relationship between LRP8 polymorphism and cardiovascular disease risk is independent of plasma cholesterol levels, but the etiology associating apoER2 dysfunction with cardiovascular disease is unknown. The premise of this application is that apoER2 dysfunctions impair smooth muscle and dendritic cell functions to adversely influence atherosclerosis progression and regression. We have shown previously that apoER2 deficiency in hyperlipidemic Ldlr-/- mice accelerates atherosclerotic lesion necrosis. ApoER2 deficiency also promotes formation of cell-poor but fibrotic-rich neointima after endothelial denudation, suggestive of excessive senescence-associated secretory smooth muscle cells. Additional in vitro data revealed that apoER2 interacts with the catalytic subunit of protein phosphatase 2 (PP2A-C) in smooth muscle cells, and its absence impairs PP2A-C functions during metaphase- anaphase transition, thereby causing cell cycle arrest, mitotic slippage, and premature cell senescence. Additional preliminary studies also found apoER2 expression in CD11c+ dendritic cells and its deficiency leads to persistent phosphorylation of the focal adhesion protein VASP and the impairment of migration and efferocytosis. One goal of this project is to establish a mechanistic framework of how the cell surface receptor apoER2 modulates these intracellular events in smooth muscle cells and dendritic cells. Another goal is to test the hypothesis that apoER2 dysfunction in CD11c+ dendritic cells impedes lesion regression and works synergistically with apoER2-deficient smooth muscle cells to accelerate lesion necrosis. Mechanistic studies proposed in Aim 1 will interrogate whether cell surface receptor binding/recycling and signaling is sufficient or if generation of an apoER2 intracellular cytoplasmic domain (ICD) peptide is required for efficient smooth muscle cell cytokinesis and dendritic cell efferocytosis and migration. Aim 2 will compare the influence of apoER2 cytoplasmic splice variants and how the R952Q mutation impact on apoER2 protection against fibrotic neointimal formation after endothelial denudation and advanced atherosclerotic lesion development in hyperlipidemic Ldlr-/- mice. Aim 3 will use tissue-specific Lrp8 knockout mice as well as bone marrow transplant approach to test the hypothesis that apoER2 dysfunction in CD11c+ dendritic cells reduces the capacity for atherosclerosis lesion regression and act synergistically with smooth muscle apoER2 deficiency to accelerate atherosclerotic lesion necrosis. These studies will offer novel mechanisms depicting how the cell surface receptor apoER2 modulates intracellular events associated with cell division and motility to impact cardiovascular disease. The information may also be leveraged to design personalized therapeutic strategy to combat cardiovascular disease in a large number of individuals with Lrp8 gene polymorphism and mutation.